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Diabetic patients with HF may particularly benefit from SGLT2 inhibitor therapy
Literature - Rådholm K, Figtree G, Perkovic V et al. - Circulation 2018;138:458–468

Introduction and methods

One of the CV risks associated with diabetes mellitus type 2 (T2DM) is heart failure (HF). Before the arrival of sodium glucose cotransporter 2 (SGLT2) inhibitors, treatment with glucose-lowering agents did not reduce HF outcomes. Dipeptidyl peptidase-4 (DPP-4) inhibitors and thiazolidinedione class have been associated with an increased risk for HF. Treatment with SGLT2 inhibitors on the other hand, have been demonstrated to reduce the risk of HF hospitalization [1-5]. The Canagliflozin Cardiovascular Assessment Study (CANVAS Program) tested the SGLT2 inhibitor canagliflozin in 10,142 T2DM patients with and without a history of HF at baseline, who were followed-up for a mean time of 188.2 weeks [5].

This analysis of the CANVAS and CANVAS-Renal studies evaluated the effects of canagliflozin on HF and a range of efficacy and safety outcomes in detail. In the CANVAS study, diabetic patients aged ≥30 years with established CVD, or aged ≥50 years at high CV risk, were randomized to receive placebo or canagliflozin 100 mg or 300 mg in a 1:1:1 ratio. In the CANVAS-R study, patients were randomized to placebo or canagliflozin 100 mg with optional up-titration to 300 mg in a 1:1 ratio. Patients with NYHA Class IV HF and those with estimated glomerular filtration rate (eGFR) ≤30 mL/min/1.73 m2 were excluded. The primary outcome for the present analysis was the composite of CV death or hospitalized HF.

Main results

65.6% of patients had a history of CV disease, and 14.4% had a history of HF at baseline.

Compared with placebo, the HRs for the primary and secondary endpoints with canagliflozin were:

  • CV death or HF hospitalization (all patients): HR: 0.78; 95%CI: 0.67–0.91
  • CV death or HF hospitalization in patients with a history of HF: HR: 0.61; 95%CI: 0.46–0.80
  • CV death or HF hospitalization in patients without a history of HF: HR: 0.87; 95%CI: 0.72–1.06
  • fatal or hospitalized HF: HR: 0.70; 95%CI: 0.55–0.89
  • hospitalized HF alone: HR: 0.67; 95%CI: 0.52–0.87
  • fatal HF: HR: 0.89; 95%CI: 0.49–1.60

Compared with placebo, the effects of canagliflozin were similar in patients with and without HF at baseline for major adverse CV events, CV death, MI, stroke, all-cause mortality, and serious decline in kidney function (all P-interaction >0.160). Patients with a history of HF at baseline had similar rates of adverse events from canagliflozin, compared to patients without HF at baseline.


In T2DM patients at high CV risk, canagliflozin reduced the risk of CV death or hospitalized HF particularly in patients with a history of HF at baseline. The risk of a number of secondary CV outcomes did not differ between those with or without HF at baseline, nor did the rate of adverse events.


1. Fitchett DH, Udell JA, Inzucchi SE. Heart failure outcomes in clinical trials of glucose-lowering agents in patients with diabetes. Eur J Heart Fail. 2017;19:43–53.

2. Monami M, Dicembrini I, Mannucci E. Dipeptidyl peptidase-4 inhibitors and heart failure: a meta-analysis of randomized clinical trials. Nutr Metab Cardiovasc Dis. 2014;24:689–697.

3. Rehman MB, Tudrej BV, Soustre J, et al. Efficacy and safety of DPP-4 inhibitors in patients with type 2 diabetes: meta-analysis of placebo-controlled randomized clinical trials. Diabetes Metab. 2017;43:48–58.

4. Fitchett D, Zinman B, Wanner C, et al. EMPA-REG OUTCOME® trial investigators. Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME® trial. Eur Heart J. 2016;37:1526–1534.

5. Neal B, Perkovic V, Mahaffey KW, et al; CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:644–657.

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